Wk 6 Metastasis Flashcards
What are the 5 steps of metastasis?
- local invasion
- intravasation
- circulation
- extravasation
- colonization
What % of human cancers are carcinomas?
80%
Normal fxns of epithelia?
- protection/barrier function
- secretion
- absorption
What happens to epithelial cells during tumor formation?
MMPs get secreted from tumor cells and modify ECM, breaking through the ECM, allowing the cancer cells to migrate
-invasion = have gone through the matrix
How is a cell’s polarity determined?
By the attachment of integrins to the ECM - determines basal side w/ apical side at other end
How is a cell’s polarity determined?
By the attachment of integrins to the ECM - determines basal side w/ apical side at other end
What is E-cadherin
protein in adherens junctions that hold cells together
What tissues are made of epithelial cells?
skin/organ lining/ducts
What tissues are made of epithelial cells?
skin/organ lining/ducts
What cells do cancer cells follow into circ?
intravasation behind macrophages
What is extravasation?
Getting out of the BV
What does ECM cause epithelial cells to do?
self-organize as polarized duct-like acini
-need ECM to survive so ones in middle will die w/o ECM contact, creating a duct
What 2 signals does the ECM send to epithelial cells?
- survival
- polarization
How is carcinogenesis different than normal epithelium?
tumor epithelial cells can survive w/o ECM contact
Summary of norm epithelium vs tumor epithelium
What is a common feature of progression in many tumors?
Loss of E-cadherin, which fascilitates cell-cell detachment
What is trapped in ECM that regulate cell proliferation, survival, polarity and migration?
growth factors
How do cancer cells move?
move along ECM fibers that are aligned by cancer-associated fibroblasts
-actin pulls on/along ECM proteins
What are the protein heterodimers that bind cells to ECM?
Integrins
intracellularly, bind to signaling proteins and cytoskeleton
extracellularly, bind to ECM
-allow for communication b/w ECM and cell
Summary of cell attachement and migration
What do we feel most often if feel a lump (think breast lump)
The ECM surrounding cancer cells
More integrin allows what?
More movement
Is cell migration sufficient for metastasis?
No, b/c still need to invade
What breaks down the ECM?
proteases: MMPs and others
Where are MMPs normally made?
Made and secreted by stromal cells (macrophages, activated fibroblasts)
-are not normally secreted by epithelial cells, but many tumor cells can overexpress MMPs OR induce stromal/immune cells to make them
How do ECM fibers look near tumors?
more linear -> rigidity and makes for a migratory highway
ECM stiffness also contributes to growth - integrins and GF receptor cross-talk
Key point
cancer cells remodel the matrix and use it to move throughout the body
End summary
What is EMT?
Epithelial cells “remember” how to migrate and invade from an essential developmental process called the epithelial- mesenchymal transition (EMT)
Besides cancer, when does EMT occur?
Gastrulation at the primitive streak
What are 6 similarities b/w developmental and cancer metastasis EMT subtypes?
What are 3 differences b/w developmental EMT and cancer metastasis?
How is cancer metastasis like wound healing?
inflammation
BV remodeling
MMPs
How does EMT assist metastasis?
How do tumor vessels look compared to normal vessels?
large, unorganized and leaky
What do tumors produce a lot of?
VEGF protein
How does the tumor microenvironment contribute to metastasis?
